Autophagy Blockage Reduces the Incidence of Pancreatic Ductal Adenocarcinoma in the Context of Mutant Trp53.

Laura Mainz,Elena M Hartmann,Katja Maurus,Sabine Roth,Mohamed A F E Sarhan,Andreas Rosenwald,Helen-Desiree Seibert,Markus E Diefenbacher,Ursula Sauer,Mathias T Rosenfeldt

doi:10.3389/fcell.2022.785252

Abstract

Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53 R172H ) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.

Highlights

pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer and has a 5-year survival rate between 5–10%
These mice were crossed to animals that contain floxed alleles of Atg7 (Atg7fl/fl) to create a cohort (Pdx1-Cre; KRasG12D/+; Trp53R172H/+; Atg7−/− (=KPC7−/−)) in which PDAC would evolve from autophagy-deficient pancreatic tissue (Figure 1A) (Komatsu et al, 2005)
In the presence of Trp53, autophagy blockage via deletion of either Atg5 or Atg7 suppresses PDAC formation, but paradoxically increases the formation of low-grade pancreatic intraepithelial neoplasias (PanINs) with impaired capacity to progress to high-grade lesions (Rosenfeldt et al, 2013; Yang et al, 2014)

Summary

Introduction

PDAC is the most frequent type of pancreatic cancer and has a 5-year survival rate between 5–10%. GEMMs that allow deletion of the essential autophagy regulating genes Atg or Atg have been instrumental in deciphering the complex relation of wild-type Trp and autophagy in de novo tumor development from healthy embryonic tissue. In human PDAC, TP53 is frequently mutated rather than allelically lost and TP53 mutants retain a certain degree of functionality with different pathobiological consequences (Saiki and Horii, 2014; Sabapathy and Lane, 2018). For this reason, we investigated the impact of autophagy blockage on de novo PDAC formation in the context of a mutant Trp allele (Trp53R172H) in mice

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Results

Conclusion